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Dissertation
Frailty across the course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): treatment and changes in frailty
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007535
Abstract
Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a chronic, indolent B cell malignancy that predominantly impacts older adults. CLL/SLL-related symptoms impair the quality of life and physical functioning of patients with CLL/SLL compared to the general population, but the impact of CLL/SLL on a patient’s frailty is unclear. Since 2014, multiple novel therapies (i.e., ibrutinib, acalabrutinib, zanubrutinib, and venetoclax) with improved efficacy and safety were approved to treat CLL/SLL which could substantially benefit older, frailer patients. However, clinical trials frequently exclude older, frailer patients and the uptake of novel therapies in clinical care settings in this patient population is unknown.
Methods: We performed two studies using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. In the first study we identified patients that initiated first-line treatment for their CLL/SLL. We then tested the effect of frailty as measured by the 16 Function-Related Indicators (FRIs) on treatment initiation in a nested case-control analysis such that cases were treatment initiators and controls were incidence density-sampled from those who had not yet received a first-line treatment. In the second study frailty was measured by total FRI score and we compared frailty at diagnosis, worsening of frailty in the 12-months after the month of diagnosis, and changes in frailty after diagnosis until the end of follow-up by cancer status (i.e., CLL/SLL vs non-cancer and CLL/SLL vs follicular lymphoma (FL)). The third study used real-world multisite electronic health record data from TriNetX. We conducted a 1:1 propensity score matched new user cohort study to compare the risk of atrial fibrillation and bleeding between acalabrutinib and ibrutinib and by age, frailty, or anticoagulant use.
Results: Overall, patients with greater general frailty were less likely to initiate treatment (negatively associated FRI ≥3 vs 0: adjusted OR: 0.60, 95% CI: 0.52-0.70); however, this relationship diminished as novel therapies were approved (pinteraction=0.031). This indicates that the introduction of novel therapies allowed more patients to be treated within 3-years of diagnosis (10.3% of patients diagnosed in 2006 to 19.6% of patients diagnosed in 2017). In both studies one and two, a set of FRIs appeared to reflect an increase in CLL/SLL disease-related activity (i.e., blood transfusion, pneumonia, bone marrow failure, sepsis, and malnutrition or unintended weight loss). In study two, patients with CLL/SLL were more likely to have worsening of frailty in the 12-months after diagnosis compared to people without cancer (adjusted OR=2.22, 95% CI: 2.17-2.28), but less likely compared to patients with FL (adjusted OR=0.76, 95% CI: 0.73-0.79). Finally, in study three, incidence rates of atrial fibrillation and bleeding per 100 person-years were higher in ibrutinib users compared to acalabrutinib users (adjusted rate difference (RD)=2.95 per 100 person-years, 95% CI: 0.85-5.04 and adjusted RD=1.90, 95% CI: 0.69-3.11, respectively). Across all but one subgroup analysis (i.e., rates of bleeding in frail patients), patients taking acalabrutinib had lower rates of atrial fibrillation and bleeding. Results suggest age and anticoagulant use might modify the risk of these outcomes.
Conclusions: Frailty is an important consideration for older patients with CLL/SLL. Our findings suggest that CLL/SLL disease activity has a role in the development of frailty with patients with chronic hematologic malignancies developing frailty after diagnosis and patients with CLL/SLL having increased CLL/SLL disease activity related frailty. However, the introduction of tolerable and efficacious novel therapies has allowed more patients to be treated, especially older, frailer patients.
Details
- Title: Subtitle
- Frailty across the course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): treatment and changes in frailty
- Creators
- Vanessa E. Siebert
- Contributors
- Elizabeth A. Chrischilles (Advisor)Ryan M. Carnahan (Committee Member)Michael A. O'Rorke (Committee Member)Christopher S. Strouse (Committee Member)Brian J. Smith (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Epidemiology
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007535
- Publisher
- University of Iowa
- Number of pages
- xiv, 192 pages
- Copyright
- Copyright 2024 Vanessa E. Siebert
- Language
- English
- Date submitted
- 12/09/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 128-147).
- Public Abstract (ETD)
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an incurable lifelong blood cancer. Patients with CLL/SLL are typically older and have other health conditions that complicate the care that they receive, but these patients are often not included in clinical trials and other research. Therefore, it is important to study access to treatments and treatment outcomes among older, frailer patients with CLL/SLL.
In this dissertation, we examined whether frailer patients with CLL/SLL are receiving the newer treatments that are associated with better outcomes and are safer. Next, we also assessed the extent to which a diagnosis of CLL/SLL contributes to frailty in older patients. Lastly, we examined if newer treatments are safe in older, frailer patients.
We found that newer treatments have allowed more patients with CLL/SLL to receive treatment, especially older, frailer patients. Older patients also benefit from the improved safety of the new treatments for CLL/SLL. Patients with CLL/SLL are more frail than people without cancers and progression of CLL/SLL also appears to lead to the development of frailty.
Frailty is important to consider for older patients with lifelong blood cancers as frailty worsens after diagnosis and frail patients tolerate newer treatments better than older treatments. Therefore, it is important for physicians to discuss frailty with patients and adjust treatment plans according to the patient (e.g., deliver newer treatments). Moreover, future studies are needed to better understand the best ways to mitigate the development of frailty after a diagnosis of CLL/SLL.
- Academic Unit
- Epidemiology
- Record Identifier
- 9984774958802771
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